A demand for a technique of an effective and rapid preparation of very fine particles in regular size has been constantly required in various industrial fields. Such fine particles in regular size have many advantages, particularly among which good flowability and little deviation in particle interaction are very advantageous in industrial application. For example, in drug industry, the particle size of a therapeutic agent greatly affects to the dissolution rate, bioavailability, formulation and the like, and as the deviation in the interaction between the particles of a therapeutic agent becomes smaller, the overall stability of the therapeutic agent becomes better.
In medicinal products, if the particle of a therapeutic agent is made into nanoscale size, the following advantages are obtained. First of all, for drugs having a small enteral absorption rate in oral administration, more absorption can be achieved and thus the bioavailability of the therapeutic agent can be increased, as compared with those of a bigger size. Furthermore, the dosage form of drugs can be various. For instance, a drug that has been administered only via oral route may be administered by inhalation. In a controlled-release drug formulation, the release rate of a therapeutic agent is a very important factor. When the particle size of the therapeutic agent is formed in nanoscale, the particle size becomes relatively more uniform, thus the release rate can become more expectable, thereby being possible to provide more effective therapeutic agent.
In order to take various advantages of uniform nanoparticles as described above, many attempts have been made to prepare an active ingredient as a nanoparticle. For this object, mechanical techniques such as crushing, grinding, milling and the like have been conventionally employed to make relatively large particles smaller. Recently in the pharmaceutical industry, a method using an air-jet mill for milling a large amount of drugs to the size range being suitable for medicinal or pharmaceutical use has been commonly used. However, according to U.S. Pat. No. 5,534,270 and Lachman, et al. [The Theory and Practice of Industrial Pharmacy, Chapter 2, “Milling”, p. 45, (1986)], such conventional mechanical processes have been generally recognized as having a limitation of possible minimum particle size of about tens of micrometers.
It was reported that nano-scale fenofibrate was obtained by a method comprising mixing fenofibrate and sodium chloride (weight ratio of 1:7) using ball mill and dry-grinding the mixture using an attritor mill [Vandym N. Mocahlin et al., Pharmaceutical Reserch, Vol. 26, No. 6, 1365˜1370. June 2009], wherein sodium chloride is a very hard material and when it is ground by ball mill, it serves as grind media and at the same time, it prevents re-coagulation of the ground fenofibrate. Furthermore, in WO 2008/126797, Hirokawa, Takashi et al. disclose a process for providing nano-scale active ingredient by mixing sodium chloride and polyol compound with active ingredient and then subjecting it to wet-milling process without grinding media. However, these processes use excessive sodium chloride and thus essentially require a step for removing sodium chloride in order to use the obtained nanoparticle in medicinal products
U.S. Pat. No. 5,202,129 discloses a method for preparing fine particles of a poorly water-soluble drug by mixing the drug with 2.5 times or more of low molecular weight saccharide or sugar alcohol and then dry-grinding the mixture. However, this method has a problem that because a large amount of saccharide is used, for actual use in medicinal products, it is required to remove the saccharide by dispersing the ground mixture in water, filtering the dispersed mixture and drying the filtered mixture.
Keiji Yamamoto et al. asserted that nanoparticles of drug may be prepared by grinding the drug along with cyclodextrin using a rod mill [Chem, Pharm, Bull. 55(3)359-363 (2007)]. They asserted that the amount of cyclodextrin used in this method is about two times of active ingredient in molar ratio, i.e. about four times in weight ratio, and that humidity for hydrating all used cyclodextrin is needed and it is disadvantageous if the humidity is too high or too low.
U.S. Pat. No. 5,145,684 discloses a method for preparing particles of a poorly water-soluble drug in a size of hundreds of nanometers by wet-milling the poorly water-soluble drug in the presence of a surfactant. This technique should be applied after preparing the drug in a particle size of 100 micrometers or less by using a conventional milling process. In this method, the time for preparing particles within the target size range depends on the mechanical device used therefor. When a ball mill is used, 5 days or longer is required. However, when a high shear media mill is used, the particles can be prepared within 1 day. However, since the nanoparticle obtained in this method is in liquid phase, in order to make it in powder type, a process of spray dry or freeze dry should be conducted. During the drying process, however, coagulation of particles occurs and when the obtained powder is re-dispersed in liquid, it is difficult to obtain a dispersion of particles in nanometer scale. In order to solve such problem, U.S. Pat. No. 5,302,401 discloses an anti-coagulation agent employed during lyophilization. Additionally, U.S. Pat. No. 6,592,903 B2 discloses use of a stabilizer, a surfactant and an anti-coagulation agent during a spray dry process. Furthermore, US Patent Application Publication No. 2003/0185869 A1 discloses an application of a wet milling technique using lysozyme as a surface stabilizer to some poorly soluble drugs. However, in this case, since the surface stabilizer is a protein, there are many restrictions in drying and accordingly only the preparation in liquid phase is disclosed.
US Patent Application Publication No. 2002/0168402 discloses a method for preparing nanoparticle using piston gap homogenization. However, in order to use piston gap homogenization, a pretreatment process using jet mill or hammer mill for grinding particle into uniform size is required. In addition, because this process is not available for highly viscose solution, it should be performed in a state where the concentration of active gradient is low.
As another conventional method, there is a recrystallization technique which provides fine particles of an active ingredient by changing the environment of a solution containing the active ingredient dissolved therein to cause the precipitation or crystallization of solute. The recrystallization technique can be practiced in two different ways: the one being comprised of dissolving a therapeutic agent in a suitable solvent and lowering the temperature, thereby changing the solubility of the therapeutic agent to precipitate particles; and the other being comprised of adding antisolvent to a solution containing the therapeutic agent dissolved therein, thereby decreasing the dissolving ability of the solvent to precipitate particles. However, most of such recrystallization techniques usually require use of organic solvent harmful to human, and flocculation or coagulation of the particles in wet condition occurs during a drying process after filtration of the precipitated particles. As a result, the final particles may not be uniform in size.
US Patent Application Publication No. 2003/0104068 A1 discloses a method for preparing fine particles by dissolving a polymer in an organic solvent, dissolving or dispersing a protein drug therein, rapidly cooling the solution to ultra-low temperature for solidification, and lyophilizing the product to provide fine powder. In this case, however, the protein drug may be denatured by the contact with an organic solvent, and the process needs the rapid cooling and lyophilizing processes and thus it is not economical.
In addition, there are techniques of reducing particle size by using emulsification. Such emulsifying methods are commonly used in cosmetic field, and provide fine particles by melting poorly water-soluble substances by heat or dissolving them in an organic solvent, and adding the melted or dissolved substances to an aqueous solution containing a surfactant dissolved therein, with stirring at high speed or with sonication to disperse the added substances. However, in this case, a step for removing water is required to provide fine particles in powder form, and many restrictions are generated during the water removal step. Furthermore, when an organic solvent is used to dissolve the poorly water-soluble substance, there always is a concern to the residual organic solvent harmful to human.
US Patent Application Publication No. 2004/0067251 A1 discloses a method for preparing fine particles by dissolving an active ingredient in an organic solvent and spraying the resulting solution into an aqueous solution containing a surfactant dissolved therein. This method uses an organic solvent, and since the prepared particles exist in an aqueous phase, a drying process is required for removing water used as solvent, to provide the particles in powder form. During the drying process, however, the coagulation of the particles occurs and thus it is hard to re-disperse them in nanoscale size.
Recently, many attempts have been made to use a supercritical fluid in preparing amorphous or nanoscale particles. Supercritical fluid is a fluid existing in liquid form at a temperature higher than its critical temperature and under pressure higher than its critical pressure. Commonly used supercritical fluid is carbon dioxide. As one of the methods using a supercritical fluid in preparing nanoparticles, rapid expansion of a supercritical solution (“RESS,” hereinafter) has been known [Tom et al. Biotechnol. Prog. 7(5):403-411. (1991); U.S. Pat. Nos. 6,316,030 B1; 6,352,737 B1; and 6,368,620 B2]. According to this method, a target solute is firstly dissolved in a supercritical fluid, and then the supercritical solution is rapidly sprayed into a relatively low-pressure condition via nozzle. Then, the density of the supercritical fluid rapidly falls down. As a result, the ability of the supercritical fluid to solubilize the solute is also rapidly reduced, and the solute is formed into very fine particles or crystallines.
Other techniques using a supercritical fluid include a gas-antisolvent recrystallization (“GAS,” hereinafter) [Debenedetti et al. J. Control. Release 24:27-44. (1993); WO 00/37169]. This method comprises dissolving a therapeutic agent in a conventional organic solvent to prepare a solution and spraying the solution through a nozzle into a supercritical fluid serving as an antisolvent. Then, rapid volume expansion occurs due to the contact between the solution and the supercritical fluid. As a result, the density and dissolving capacity of the solvent decrease, thereby causing extreme supersaturation and forming seeds or particles of the solute.
U.S. Pat. No. 6,630,121 discloses a method for preparing fine particles by nebulizing a solution containing active ingredients to fine particles by using a supercritical fluid, and drying the resulted particles with a dry gas. This method can be used regardless of the solubility of the active ingredients to the supercritical fluid. WO 02/38127 A2 discloses a method using SEDS (Solution Enhanced Dispersion by Supercritical fluids) technique for preparing fine particles of active ingredients and coating the resulted fine particles with an additive such as a polymer. Furthermore, U.S. Pat. No. 6,596,206 B2 discloses a technique of preparing fine particles of active ingredients by dissolving the active ingredients in an organic solvent and applying an ultrasonic wave to the resulted solution so that the solution can be sprayed in a form of fine particles into a supercritical fluid.
However, the prior arts using supercritical fluid have problems in uniformity between the production batches and in commercial production. In order to resolve such problems in the prior techniques using supercritical fluid, the methods using a supercritical fluid for preparing nano-powder of active ingredient wherein solid fat or the like is used as a solvent were suggested in Korean Patent Application Publication Nos. 2005-0054819, 2007-0107879 and 2007-0107841.